Mental and behavioural disorders are among the leading causes of disability, accounting for more than 37 percent of years of life lived with disability (YLD) amongst adults aged 15 years and older worldwide, and as illness likely to represent an increasingly greater health, societal and economic problem in the coming years (Lopez and Murray 1998). Mental and behavioural disorders are defined in ICD10, Chapter V, Blocks F00-F99 (Mental and behavioural disorders) from World Health Organization, and include for example depression and major depressive disorders, obsessive compulsive disorder, schizophrenia, visual and auditory hallucinations, eating disorder, anxiety disorders, and bipolar disorder (manic depressive illness). These disorders are common, severe, chronic, and often life-threatening illness. Suicide is estimated to be the cause of the death in up to 15% of the individuals with disorders such as major depressive disorders and bipolar disorder, and many other deleterious health-related effects have been recognized (Michelson, Stratakis et al. 1996; Musselman, Evans et al. 1998; Ciechanowski, Katon et al. 2000; Schulz, Beach et al. 2000; Kupfer 2005). It is increasingly being recognized that these disorders are systemic diseases with deleterious effects on multiple organ systems. For example, major depressive disorder represents a major risk factor for both the development of cardiovascular disease, as well as for death after an index myocardial infarction (Musselman, Evans et al. 1998). A recent study has suggested that the magnitude of the increased mortality risk conferred by high depressive symptoms was similar to that of stroke and congestive heart failure (Schulz, Beach et al. 2000).
Altered neuronal activity and in particular impairment in synaptic plasticity is believed to underlie the pathophysiology of mental and behavioural disorders such as but not limited to schizophrenia, depression, and bipolar disorder (Manji, Drevets et al. 2001; Lu and Martinowich 2008). It is believed that distinct neuronal activities in the mammalian central nervous system underlie the variety of specific brain functions observed in animals and humans. Subcellular mechanisms may shape the activity of individual neurons, which may again be integrated into functional cell assemblies (Buzsaki and Draguhn 2004). The function of these cell assemblies may be further integrated into functionally meaningful mechanisms, which manifest as various forms of behavior. Certain subcellular mechanisms are critical for shaping the neuronal activity, including the intrinsic excitability of single neurons, as well as basic synaptic properties, and synaptic plasticity. All these mechanisms can coincide across neuronal networks to generate the brain oscillations that are typical for mammalian brain function (Buzsaki and Draguhn 2004). In humans, if these precisely controlled brain oscillations break down, it may lead to severe mental and behavioural symptoms, which today are difficult to treat. In this context, neuronal activity covers the electrical activity in subcellular compartments, in single neurons or assemblies thereof, including the supra- or subthreshold synaptic responses and plasticity thereof, the membranel excitability in cells in neuronal tissues, the changes in intracellular ion concentrations, or transmembranal ion currents, measured by single cell imaging or single-channel, excised-patch, or whole-cell patch-clamp recordings, or by intra- or extracellular recordings, in vitro or in vivo, and behavioral correlates thereof.
Molecular mechanisms of synaptic plasticity involve initially the modification of existing synaptic proteins resulting in altered synaptic function. It also depends on second messenger neurotransmitters regulating gene transcription and changes in the levels of key proteins at the synapses. This activity-dependent mechanism takes longer and lasts longer, and is believed to be a fundamental mechanism for longlasting memory storage and processing in the brain. Long-lasting changes in the efficacy of synaptic connections between two neurons can involve the strengthening (denoted long-term potentiation or LTP) or weakening of synaptic contacts (denoted long-term depression or LTD). Traditionally, LTP has been regarded as the main mediator of spatial memory storage in the hippocampus, whereas LTD has been assigned a role in signal-to-noise regulation and in erasing memories. However, accumulating evidence suggest that LTD also has a role in learning and memory (Kemp and Manahan-Vaughan 2007). Importantly, the induction of LTD seems to be related to the development of mood disorders. For example, LTD is facilitated in animals exposed to mild naturalistic stress and in animal models of depression (Xu, Anwyl et al. 1997; Holderbach, Clark et al. 2007).
Neurotrophic factors are small soluble proteins that function as key regulators of neuronal activity including synaptic plasticity and neuronal survival through the interaction with cell surface receptor tyrosine kinases. For example, activity-dependent secretion of brain-derived neurotrophic factor (BDNF) is a key step in the induction of long-term synaptic modification (Poo 2001). In the hippocampus, BDNF is known to play an important role in the induction of early-phase LTP through its regulated release from the presynaptic side and its subsequent interaction with the receptor tyrosine kinase TrkB on the postsynaptic side (Nagappan and Lu 2005). Similarly, the release of the proform of BDNF (proBDNF) and the cleavage by extracellular proteinases into mature BDNF are required for the induction of late-phase LTP (Pang, Teng et al. 2004). On the other hand, the interaction of uncleaved proBDNF with the receptor p75NTR results in the induction of LTD (Woo, Teng et al. 2005). Along these lines, BDNF +/− mice and knock-in mice with defective BDNF secretion show a clear behavioral phenotype including anxiety and cognitive dysfunction (Chen, Jing et al. 2006; Einat and Manji 2006).
BDNF also modulates neuronal activity in general, for example, the activity of GABAergic neurons. GABA (gamma-amino butyric acid) is the major inhibitory neurotransmitter in the mammalian brain. GABA is released from approximately 20% of the neurons in the cerebral cortex (Somogyi, Tamas et al. 1998), and mediates fast synaptic inhibition via ubiquitously expressed GABAA receptors at synaptic contacts (Farrant and Nusser 2005). By rapidly opening Cl-channels associated with the GABAA receptor, GABA orchestrate the rhythms of the cortical networks, which is believed to underlie important functions such as sensory processing, memory formation and higher cognitive functions. As the brain rhythms break down in disorders such as epilepsy, depression, and schizophrenia, a defective GABA system is thought to play a fundamental role in the development and maintenance of these incurable mental and behavioural disorders (Lewis, Hashimoto et al. 2005). GABAA receptor-mediated inhibition can be modulated by several mechanisms, including changes in the firing rate of GABAergic interneurons, the kinetics of quantal release, alterations in synaptic cleft morphology postsynaptic modification at the GABAA receptor level (Ben-Ari and Cossart 2000), and shift in the electrochemical gradients for the permanent anions (Kaila 1994). Mature BDNF modulates GABAergic synaptic transmission via several—if not all—of these mechanisms. BDNF reduces GABA release probability at the terminals (Frerking, Malenka et al. 1998; Olofsdotter, Lindvall et al. 2000), attenuates GABAA receptor surface expression (Henneberger, Juttner et al. 2002; Hewitt and Bains 2006), and abates the driving force of Cl— electrochemical potential via inhibition of KCC2 (K—Cl cotransporter 2) (Rivera, Li et al. 2002). The modulating effect of BDNF on GABAergic transmission has also been shown in the dentate gyrus. The frequency of mlPSCs (Olofsdotter, Lindvall et al. 2000) and sIPSCs (Holm et al., submitted manuscript) are attenuated by endogenous and exogenous BDNF. Finally, mature BDNF reduces the excitability of basket cells suggesting that this mechanism participates in the reduction of sIPSCs via TrkB receptors (Holm et al., submitted manuscript).
Sortilin
Sortilin, the archetypal member of the Vps10p-domain receptor family is occasionally also referred to as neurotensin receptor 3 (NTR3), Glycoprotein 95 (Gp95) or 100 kDa NT receptor. Human Sortilin is accessed in Swiss Prot under ID No. Q99523. Sortilin, (SEQ ID NO. 1) is a type I membrane receptor expressed in a number of tissues, including the brain, spinal cord, testis, liver and skeletal muscle (Petersen, Nielsen et al. 1997; Hermans-Borgmeyer, Hermey et al. 1999). Sortilin belongs to a family of receptors comprising Sortilin, SorLA (Jacobsen, Madsen et al. 1996), SorCS1, SorCS2 and SorCS3. All the receptors in this family share the structural feature of an approximately 600- amino acid N-terminal domain with a strong resemblance to each of the two domains, which constitute the luminal portion of the yeast sorting receptor Vps10p (Marcusson, Horazdovsky et al. 1994). The Vps10p-domain (Vps10p-D) that among other ligands binds neurotrophic factors and neuropeptides (Mazella, Zsurger et al. 1998; Munck Petersen, Nielsen et al. 1999; Nykjaer, Lee et al. 2004; Westergaard, Sorensen et al. 2004; Teng, Teng et al. 2005), constitutes the entire luminal part of Sortilin (sSortilin) and is activated for ligand binding by enzymatic propeptide cleavage (Mazella, Zsurger et al. 1998; Munck Petersen, Nielsen et al. 1999). Sortilin is a multifunctional type-1 receptor capable of endocytosis as well as intracellular sorting (Marcusson, Horazdovsky et al. 1994; Mazella, Zsurger et al. 1998; Munck Petersen, Nielsen et al. 1999), and as shown recently, it also engages in signaling by triggering proneurotrophin-induction of p75NTR-mediated neuronal apoptosis (Nykjaer, Lee et al. 2004; Teng, Teng et al. 2005; Jansen, Giehl et al. 2007; Nakamura, Namekata et al. 2007). Sortilin is synthesized as a proprotein, which is converted to mature Sortilin by enzymatic cleavage and removal of a short N-terminal propeptide. Only the mature receptor binds ligands and interestingly, all its known ligands, e.g. Neurotensin (NT), lipoprotein lipase, the proforms of nerve growth factor-β (proNGF) and brain derived neurotrophic factor (proBDNF), receptor associated protein (RAP), and its own propeptide, compete for binding (Munck Petersen, Nielsen et al. 1999; Nielsen, Jacobsen et al. 1999; Nykjaer, Lee et al. 2004; Teng, Teng et al. 2005), indicating that the diverse ligands target a shared or partially shared binding site. NT is a tridecapeptide, which binds to Sortilin, SorLA and the two G-protein coupled receptors NTR1 and NTR2 (Tanaka, Masu et al. 1990; Chalon, Vita et al. 1996; Mazella, Zsurger et al. 1998; Jacobsen, Madsen et al. 2001). The physiological role of NT in relation to Sortilin has not been fully elucidated (Vincent, Mazella et al. 1999), still NT is an important tool, as it inhibits all other ligands from binding to the Sortilin Vps10p-D. Sortilin has been the suggested to be involved in the regulation of extracellular BDNF availability, possibly by the intracellular sorting of proBDNF (Chen, leraci et al. 2005). In fact, Sortilin was suggested to have reduced affinity for the Va166Met variant of BDNF previously associated with poor memory function, anxiety-related behavior, and bipolar disorder (Neves-Pereira, Mundo et al. 2002; Egan, Kojima et al. 2003; Chen, Jing et al. 2006).
SorLA
Sorting protein-related receptor abbreviated SorLA (Swiss prot ID no Q92673), also known as LR11, is a 250-kDa type-1 membrane protein and the second member identified in the Vps10p-domain receptor family. SorLA, like sortilin, whose lumenal domain consists of a Vps10p domain only, is synthesized as a proreceptor that is cleaved by furin in late Golgi compartments. It has been demonstrated that the truncation conditions the Vps10p domain for propeptide inhibitable binding of neuropeptides and the receptor-associated protein. It has been demonstrated (Jacobsen, Madsen et al. 2001) that avid binding of the receptor-associated protein, apolipoprotein E, and lipoprotein lipase not inhibited by propeptide occurs to sites located in other lumenal domains. In transfected cells, about 10% of full-length SorLA is expressed on the cell surface capable mediating endocytosis. The major pool of receptors is found in late Golgi compartments, and interaction with newly synthesized ligands has been suggested. SorLA is highly expressed in distinct cell types throughout the nervous system both during development and in the adult organism (Kanaki, Bujo et al. 1998; Motoi, Aizawa et al. 1999; Offe, Dodson et al. 2006). Interestingly, SorLA levels are reduced in the sporadic form of Alzheimer's disease (Scherzer, Offe et al. 2004; Dodson, Gearing et al. 2006; Sager, Wuu et al. 2007) and inherited mutations in the SorLA gene are genetically linked to late-onset Alzheimer's disease (Rogaeva, Meng et al. 2007). Importantly, SorLA has been shown to mediate high affinity binding and sorting of amyloid precursor protein, and to confer protection against Abeta generation (Andersen, Reiche et al. 2005; Offe, Dodson et al. 2006; Spoelgen, von Arnim et al. 2006; Rogaeva, Meng et al. 2007).
SorCS1-3
SorCS1 (Swiss prot ID no Q8WY21), SorCS2 (Swiss prot ID no Q96PQ0) and SorCS3 (Swiss prot ID no Q9UPU3) constitute a subgroup of mutually highly similar proteins containing both a Vps10p-D and a leucine-rich domain bordering the transmembrane domain (Westergaard, Sorensen et al. 2004; Westergaard, Kirkegaard et al. 2005). SorCS1-3 are all prominently expressed throughout the nervous system (Hermey, Riedel et al. 1999; Hermey, Riedel et al. 2001; Hermey, Schaller et al. 2001; Rezgaoui, Hermey et al. 2001; Hermey, Keat et al. 2003) but are differentially expressed and regulated by synaptic plasticity (Hermey, Plath et al. 2004). Similar to SorLA and Sortilin, SorCS1 binds to its propeptide but no binding to either RAP or NT was observed (Hermey, Keat et al. 2003). SorCS1 and SorCS3 both bind to platelet-derived growth factor-BB while no SorCS2 ligand has been described (Hermey, Sjogaard et al. 2006). SorCS3 also binds to the prodomain of proNGF but unlike Sortilin and SorLA, it does not require propeptide cleavage in order to bind ligands (Westergaard, Kirkegaard et al. 2005). SorCS1 may play an important role outside the nervous system as a region on the gene was identified as a type 2 diabetes quantitative trait locus in mice (Clee, Yandell et al. 2006), and variations in the human SorCS1 gene are associated with diabetes-related traits (Granhall, Park et al. 2006; Goodarzi, Lehman et al. 2007). Interestingly, single nucleotide polymorphisms (SNP) in the SorCS2 gene are found to be associated with a particular high risk of developing bipolar disorder (Baum, Akula et al. 2008).
State of the Art
Although a number of drugs are already available for the treatment of mental and behavioural disorders, all have complex indirect mechanism of action, and are aimed at alleviating the symptoms rather than at treating the underlying cause of the disease. Instead, it is generally believed that drugs that target the signaling pathways that regulate synaptic plasticity should be developed as long-term treatments for mental and behavioural disorders (Manji, Drevets et al. 2001). In fact, chronic administration of antidepressants and lithium exert major effects on such signalling pathways likely by increasing the expression of neurotrophic factors, notably BDNF (Manji, Drevets et al. 2001; Duman and Monteggia 2006; Martinowich, Manji et al. 2007). Extensive experimental and clinical data suggest a central function for BDNF in mental and behavioural disorders. For example, polymorphisms in the BDNF gene correlate with mental and behavioural disorders such as schizophrenia, depression, and bipolar disorder (Neves-Pereira, Mundo et al. 2002; Schumacher, Jamra et al. 2005). In addition, BDNF serum levels are decreased in depressive and manic episodes of patients suffering from bipolar disorder but increased in schizophrenic patients (Gama, Andreazza et al. 2007). Also, BDNF levels are lower in post-mortem brain tissue from depressed patients compared to normal human subjects but higher in those who were taking antidepressants at the time of death (Chen, Dowlatshahi et al. 2001). Furthermore, direct hippocampal infusions of BDNF produce antidepressant effects in rodents (Siuciak, Lewis et al. 1997; Shirayama, Chen et al. 2002).